GB2168979A - Bis (triphenylphosphine) hydrazino methoxyrhodium (i) - Google Patents
Bis (triphenylphosphine) hydrazino methoxyrhodium (i) Download PDFInfo
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- GB2168979A GB2168979A GB08526784A GB8526784A GB2168979A GB 2168979 A GB2168979 A GB 2168979A GB 08526784 A GB08526784 A GB 08526784A GB 8526784 A GB8526784 A GB 8526784A GB 2168979 A GB2168979 A GB 2168979A
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- Prior art keywords
- catalyst
- triphenylphosphine
- reaction
- deoxy
- hydrogenation
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- -1 Bis (triphenylphosphine) hydrazino methoxyrhodium Chemical compound 0.000 title description 3
- 239000003054 catalyst Substances 0.000 claims abstract description 35
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims abstract description 34
- 238000005984 hydrogenation reaction Methods 0.000 claims abstract description 16
- 150000001875 compounds Chemical class 0.000 claims abstract description 12
- 230000000707 stereoselective effect Effects 0.000 claims abstract description 4
- 238000006243 chemical reaction Methods 0.000 claims description 13
- 238000000034 method Methods 0.000 claims description 6
- 239000002904 solvent Substances 0.000 claims description 6
- 229910052799 carbon Inorganic materials 0.000 claims description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 2
- 125000004432 carbon atom Chemical group C* 0.000 claims description 2
- IWVCMVBTMGNXQD-UHFFFAOYSA-N terramycin dehydrate Natural products C1=CC=C2C(O)(C)C3C(O)C4C(N(C)C)C(O)=C(C(N)=O)C(=O)C4(O)C(O)=C3C(=O)C2=C1O IWVCMVBTMGNXQD-UHFFFAOYSA-N 0.000 claims 1
- SGKRLCUYIXIAHR-AKNGSSGZSA-N (4s,4ar,5s,5ar,6r,12ar)-4-(dimethylamino)-1,5,10,11,12a-pentahydroxy-6-methyl-3,12-dioxo-4a,5,5a,6-tetrahydro-4h-tetracene-2-carboxamide Chemical compound C1=CC=C2[C@H](C)[C@@H]([C@H](O)[C@@H]3[C@](C(O)=C(C(N)=O)C(=O)[C@H]3N(C)C)(O)C3=O)C3=C(O)C2=C1O SGKRLCUYIXIAHR-AKNGSSGZSA-N 0.000 abstract description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 14
- 239000010948 rhodium Substances 0.000 description 14
- 229910052703 rhodium Inorganic materials 0.000 description 13
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 description 13
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- XYFCBTPGUUZFHI-UHFFFAOYSA-N phosphine group Chemical group P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 8
- 239000011541 reaction mixture Substances 0.000 description 8
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 5
- 239000001257 hydrogen Substances 0.000 description 5
- 229910052739 hydrogen Inorganic materials 0.000 description 5
- 238000002360 preparation method Methods 0.000 description 5
- QBERHIJABFXGRZ-UHFFFAOYSA-M rhodium;triphenylphosphane;chloride Chemical compound [Cl-].[Rh].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 QBERHIJABFXGRZ-UHFFFAOYSA-M 0.000 description 5
- 239000002253 acid Substances 0.000 description 4
- 239000012298 atmosphere Substances 0.000 description 4
- 229960003722 doxycycline Drugs 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- 229910000073 phosphorus hydride Inorganic materials 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 239000007858 starting material Substances 0.000 description 4
- XIYOPDCBBDCGOE-IWVLMIASSA-N (4s,4ar,5s,5ar,12ar)-4-(dimethylamino)-1,5,10,11,12a-pentahydroxy-6-methylidene-3,12-dioxo-4,4a,5,5a-tetrahydrotetracene-2-carboxamide Chemical compound C=C1C2=CC=CC(O)=C2C(O)=C2[C@@H]1[C@H](O)[C@H]1[C@H](N(C)C)C(=O)C(C(N)=O)=C(O)[C@@]1(O)C2=O XIYOPDCBBDCGOE-IWVLMIASSA-N 0.000 description 3
- FQSJTDWWYNDQKL-UHFFFAOYSA-N N(N)CO[Rh].C1(=CC=CC=C1)P(C1=CC=CC=C1)C1=CC=CC=C1.C1(=CC=CC=C1)P(C1=CC=CC=C1)C1=CC=CC=C1 Chemical compound N(N)CO[Rh].C1(=CC=CC=C1)P(C1=CC=CC=C1)C1=CC=CC=C1.C1(=CC=CC=C1)P(C1=CC=CC=C1)C1=CC=CC=C1 FQSJTDWWYNDQKL-UHFFFAOYSA-N 0.000 description 3
- 239000004098 Tetracycline Substances 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 238000009905 homogeneous catalytic hydrogenation reaction Methods 0.000 description 3
- 239000003446 ligand Substances 0.000 description 3
- 229940042016 methacycline Drugs 0.000 description 3
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 239000012429 reaction media Substances 0.000 description 3
- 230000035484 reaction time Effects 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- 229940040944 tetracyclines Drugs 0.000 description 3
- JOXIMZWYDAKGHI-UHFFFAOYSA-M toluene-4-sulfonate Chemical compound CC1=CC=C(S([O-])(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-M 0.000 description 3
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- 229910021604 Rhodium(III) chloride Inorganic materials 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 239000003638 chemical reducing agent Substances 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 2
- 238000007037 hydroformylation reaction Methods 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- SONJTKJMTWTJCT-UHFFFAOYSA-K rhodium(iii) chloride Chemical compound [Cl-].[Cl-].[Cl-].[Rh+3] SONJTKJMTWTJCT-UHFFFAOYSA-K 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 229910001220 stainless steel Inorganic materials 0.000 description 2
- 239000010935 stainless steel Substances 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- 239000011995 wilkinson's catalyst Substances 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- CBGLPKFDLLCLDU-UHFFFAOYSA-M Cl[Rh].C1(=CC=CC=C1)P(C1=CC=CC=C1)C1=CC=CC=C1.C1(=CC=CC=C1)P(C1=CC=CC=C1)C1=CC=CC=C1 Chemical compound Cl[Rh].C1(=CC=CC=C1)P(C1=CC=CC=C1)C1=CC=CC=C1.C1(=CC=CC=C1)P(C1=CC=CC=C1)C1=CC=CC=C1 CBGLPKFDLLCLDU-UHFFFAOYSA-M 0.000 description 1
- 230000005526 G1 to G0 transition Effects 0.000 description 1
- 238000004566 IR spectroscopy Methods 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 101100030361 Neurospora crassa (strain ATCC 24698 / 74-OR23-1A / CBS 708.71 / DSM 1257 / FGSC 987) pph-3 gene Proteins 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 239000003060 catalysis inhibitor Substances 0.000 description 1
- 150000001793 charged compounds Chemical class 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 239000007857 degradation product Substances 0.000 description 1
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 1
- 229910000397 disodium phosphate Inorganic materials 0.000 description 1
- 235000019800 disodium phosphate Nutrition 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 238000007172 homogeneous catalysis Methods 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 238000002329 infrared spectrum Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 239000011872 intimate mixture Substances 0.000 description 1
- 238000003760 magnetic stirring Methods 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 150000002739 metals Chemical class 0.000 description 1
- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 238000004816 paper chromatography Methods 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 238000010926 purge Methods 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000011924 stereoselective hydrogenation Methods 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 235000019364 tetracycline Nutrition 0.000 description 1
- 150000003522 tetracyclines Chemical class 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F15/00—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table
- C07F15/0006—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table compounds of the platinum group
- C07F15/0073—Rhodium compounds
- C07F15/008—Rhodium compounds without a metal-carbon linkage
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Catalysts (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The new compound bis(triphenylphosphine)hydrazinomethoxyrhodium (I) is a catalyst for the stereo-specific hydrogenation of demethyl-6-deoxy-6-methylene-5-hydroxytetracycline to alpha -6-deoxy-5-hydroxy-tetracycline.
Description
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GB 2 168 979 A
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SPECIFICATION
A rhodium catalyst and its application
5 The present invention refers to a compound, bis(triphenylphosphine)-hydrazinomethoxyrhodium (I),
which is a homogeneous hydrogenation rhodium catalyst, particularly useful in the hydrogenation of the exocyclic methylene group of 6-demethyl-6-deoxy-6-methylene-tetracyclines to prepare a-6-deoxy-tetracyclines.
The so-called "Wilkinson catalyst", i.e. tris(triphenylphosphine)-chlororhodium (I) complex is a 10 homogeneous rhodium hydrogenation catalyst and was first described by T. F. Young, J. A. Osborne,
F. HJardine and G. Wilkinson in Chem. Comm., p. 131 (1965), whilst bis(triphenylphosphine)-chlororhodium (I) was described by by M. A. Bennett and P. A. Longstaff, Chem. &ind., p. 846 (1965).
U.S. Patent 3,463,830 (filed in 1966) describes the preparation of zero valent platinum and palladium catalysts, by the reduction of these metals from oxidation state II by the use of the reducing agent, hydrazine. 15 The function of the hydrazine is merely as a reducing agent, and it is not incorporated into the catalyst so prepared. As will be described hereinbelow, the compound of the present invention differfrom those of U.S. Patent 3,463,830 in that the hydrazine is incorporated into the rhodium complex as a ligand, and surprisingly the rhodium is not reduced to the zero oxidation state.
U.S. Patent 3,956,177 (filed in 1971) describes compositions useful as hydroformylation catalysts, 20 prepared by contacting an organorhodium halide with a hydrazine and a phosphorus-containing adjuvant, to form an intimate mixture thereof. It is stated in the specification that these catalysts are not compounds formed by the components of the mixture, and they are not described as useful for the hydrogenation of carbon/carbon double bonds, but as catalysts for hydroformylation reactions.
U.S. Patent 4,001,321 (filed in 1974) describes the preparation of a homogeneous hydrogenation catalyst, 25 >-e. dicarboxylato(triphenylphosphine)rhodium (II) or dicarboxylato(substituted triphenylphosphine)rho-dium (II) for the stereo-selective hydrogenation of methacycline.
U.S. Patent 3,962,131 (filed in. 1975) describes a homogeneous hydrogenation catalyst, which is obtained by refluxing rhodium trichloride and sodium acetate in methanol, and then reacting the resulting reaction mixture with triphenylphosphine. This catalyst, the formula of which is unknown, but distinct from those of 30 U.S Patent 4,001,321, is effective in the hydrogenation of the exocyclic methylene group of methacycline, yielding a-6-deoxyoxytetracycline.
European Patent Specification 86046 describes a homogeneous rhodium catalyst, containing, besides a tertiary phosphine, a hydrazine as ligand. The incorporation of a hydrazine as a ligand into the complex has the unexpected result of improving the regio-specificity and stereo-specificity of the catalyst for the 35 hydrogenation of exocyclic methylene groups, such as for instance in the hydrogenation of methacycline to a-6-deoxy-oxytetracycline. By such improvements a significant reduction of the amount of the catalyst employed in relation to the substrate is possible, as well as allowing the reduction of the pressure and of the reaction time.
This application however did not provide specific formulae for the catalysts therein prepared, which could 40 cause some difficulty in the decision as to the quantity of catalyst to be used, without the accomplishment of a series of experimental trials. Further, it has been verified that the processes as such did not allow the obtention of catalysts in a completely pure form, i.e. the catalysts were contaminated by oxygen absorbed during their preparation, thus it was not possible to establish their exact structural formulae. The present invention effectively overcomes this problem, by the use of a complex with a uniform and well-defined 45 composition.
According to the present invention there is provided a compound, bis(triphenylphosphine)hydrazi-nomethoxyrhodium (I), and its use in an improved process for the stereospecific hydrogenation of 6-demethyl-6-deoxy-6-methylene-5-hydroxytetracycline, in the presence of a catalyst, in order to prepare a-6-deoxy-5-hydroxytetracycline in highyield and purity, characterised by the fact that the catalyst is 50 bis(triphenylphosphine)-hydrazinomethoxyrhodium (I), eventually in the presence of triphenylphosphine, at a pressure of 1 to 10 kg/cm2 and a temperature from 20°Cto 95°C, in the presence of a solvent inert in the reaction, such as a lower alcohol containing from 1 to 6 carbon atoms.
We have now found that the problems associated with the processes of European Patent Specification 86046, can be reduced or overcome by the use of degassed solvents, performing the reaction in the presence 55 of an inert atmosphere, such as nitrogen, and drying in an inert atmosphere.
In this manner, the compound of the present invention, bis(triphenylphosphine)hydrazinomethoxyrho-dium (I), substantially un-contaminated by oxygen, is obtained. Another advantage of the compound of the present invention is that it more easily permits the determination of the effective minimum amount of rhodium that can be used per unit of the substrate to be hydrogenated. Taking into consideration the high 60 price of rhodium, it has been found necessary to employ the effective minimum amount of the catalyst.
The catalyst of the present invention offers advantages not only in the field of tetracyclines, but also in other fields where stereospecific homogeneous catalysis is required.
The catalyst of the present invention is prepared by reacting tris-(triphenylphosphine)chlororhodium (I) with hydrazine hydrate, which is normally present in an excess based upon the number of moles of rhodium 65 present. It is preferred that 3 moles of the hydrazine are used for each mole of rhodium. It is also possible
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that the tris(triphenylphosphine)-chlorohodium (I) is substituted by the in situ reaction product of rhodium trichloride and triphenylphosphine.
The reaction medium is degassed methanol, and the reaction is carried out between 0°C and 100°C, preferably at the reflux temperature of the reaction medium. The reaction is carried out under an inert 5 atmosphere, preferably nitrogen, and can be followed visually in that the initial colour of the reaction mixture is purple and that of the catalyst of the present invention is orange/yellow. Thus, the time for the reaction, which is dependant on the temperature, can be judged quite easily. It is typically between a few minutes and two hours.
When the reaction is judged complete, the catalyst is obtained by conventional means, followed by drying 10 under an inert atmosphere.
Naturally, any amount of rhodium eventually remaining in the mother liquors of the above preparation can easily be recovered, practically without loss, by conventional methods and recycled.
Thus, the product of the present invention, as obtained in Example 1 was shown, by a combination of mass spectrometry, infra-red spectroscopy and nuclear magnetic resonance to have the following 15 structure:-
^J
och3
The present invention also concerns the preparation of a-6-deoxy-5rhydroxytetracycline (doxycycline) by 30 hydrogenating 6-methyl-6-deoxy-6-methylene-5-hydroxytetracycline or an acid addition salt thereof, in a reaction inert solvent, in the presence of the compound of the present invention, bis(triphenylphosphine)hy-drazinomethoxyrhodium (I) as catalyst, prepared as previously described.
The hydrogenation can be carried out in a traditionally designed stainless steel hydrogenator. The reaction temperature is preferably between 20°G and 95°C, preferably between 60°C and 90°C. The reaction is too slow 35 at temperatures below 20°C and decomposition of both starting material and product startsto occur above 95°C. The pressure of hydrogen used in the reaction is preferably between 1 kg/cm2 and 10 kg/cm2.
The reaction time is dependant on the amount of catalyst used, the type of hydrogenator, the reaction temperature and the hydrogen pressure. A satisfactory reaction time is from about 4 to 10 hours, but satisfactory results and high yields can be obtained even after 16 hours of hydrogenation. 40 6-Demethyl-6-deoxy-6-methylene-5-hydroxytetracycline can be prepared by any of the known processes, for example according to U.S. Patent 3,849,491, but should not contain impurities which may act as catalyst inhibitors.
The starting material is added in the form of an acid addition salt, such as hydrochloride or p-toluenesulphonate, but other acid addition salts can be used provided that the acid is not a catalyst 45 inhibitor.
The hydrogenation is stopped when the rate of consumption of hydrogen drops drastically. The reaction mixture, once the hydrogenation is completed, contains nearly exclusively the a-epimer, does not contain unreacted starting material or only traces, the amount of by-products or degradation products is negligible and the (3-epimer is less than 1%, and usually it is around 0.1 %
50 It has been observed that the addition of a small amount of a tertiary phosphine, preferably triphenylphosphine, to the reaction mixture, prior to starting the hydrogenation, will accelerate the rate of hydrogen consumption, facilitate completion of the reaction and increase the yield up to 100%. The preferred excess of the tertiary phosphine in relation to the catalyst is about 10 moles/mole, although it can be increased to above 50 moles/mole without detriment to the yield of purity of the product. The optimum 55 amount of additional tertiary phosphine can easily be determined for a the catalyst by running a few experiments.
The purity of the reaction mixture thus obtained is such thatthe doxycycline can be crystallised directly from said reaction mixture by adding p-toluenesulphonic acid in excess, on condition that the solvent in the reaction medium is a non-solvent for the doxycycline p-toluenesulphonate salt thus formed; such as a 60 solvent is preferably methanol.
The purity so obtained is usually superior to 99% calculated on the dry basis. The doxycycline p-toluenesulphonate can subsequently be transformed directly into the hydrochloride hemiethanolate hemihydrate by conventional processes with a yield nearto stoichiometric.
The following examples are given byway of illustration of the present invention, without in anyway 55 limiting the scope thereof.
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GB 2 168 979 A
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Example 1
Catalyst: Tris(triphenylphosphine)chlororhodium (I) (0.48 g; 0.52 mmoles) was refluxed under nitrogen for 90 minutes with hydrazine hydrate 30 (76 (xl; 1.56 mmoles) in dry, degassed methanol (20 ml). The yellow orange solution was cooled to yield a yellow solid.
5 The infra-red spectrum of this yellow solid showed the presence of triphenylphosphine, contained a band 5 around 3300 cm"1 due to stretching of the N - H bonds and a band at 420-430 cm"1 due to the presence of the metal bonded methoxy group. There was no band in the 250-400 cm"1 region that could be assigned to a rhodium-chlorine bond (as compared with the band at 320 cm"1 for the Wilkinson catalyst). Additionally, the absence of chlorine in the compound was confirmed by a negative spot test. The nuclear magnetic 10 resonance spectrum showed one sharp peak at 83.4, assigned to the protons of the methoxy group and a 10 complex region at 57-7.5 due to the protons of the phenyl groups. The mass spectrum did not show a molecular ion, the highest peak being for Rh(PPh3)2. These results show the structural identity of the compound to be bis(triphenylphosphine)-hydrazinomethoxyrhodium (I).
Hydrogenation: 25 mg (36.20 ^moles) of the thus obtained catalyst in methanol (20 ml) was added to a 15 stainless steel hydrogenation apparatus under magnetic stirring, containing 6-demethyl-6-deoxy-6- 15 :
methylene-5-hydroxytetracycline hydrochloride (7.38 g; 15.41 mmoles) and triphenylphosphine (0.1 g; 0.38 mmoles) in methanol (40 ml). After purging it with nitrogen, hydrogen was added to a pressure of 8 kg/cm2 and the reaction mixture was heated up to 89°C. After 5h30m the consumption dropped, and 1 hour later the reaction mixture was cooled down. It was filtered through a G4 glass-filter, then p-toluenesulphonicacid (3.3 20 g; 17.35 mmoles) was added to the filtrate which was then stirred. The a-6-deoxy-oxytetracycline 20
p-toluenesulphonate thus formed was filtered, washed with acetone and dried. The product weighed 8.90 g, and had a purity of 99.5%. No (3-isomer or starting material were detectable by circular paper chromatography ("Schleicher &SchulI" paper N°2045 B, 265 mm, ref, N° 381804; stationary phase: 100 ml of a solution of 0.1 M citric acid and 40 ml of 0.2M anhydrous disodium phosphate were mixed to make a 25 buffer with pH 3.5; mobi'e phase: nitromethane:chlorofomn:pyridine-20:10:3). 25
Claims (2)
1. The compound bis(triphenylphosphine)hydrazinomethoxyrhodium (I)
30
2. An improved process for the stereospecific hydrogenation of 6-demethyl-6-deoxy-6-methylene-5- 30 hydroxytetracycline, in the presence of a catalyst, in order to prepare a-6-deoxy-5-hydroxytetracycline in high yield and purity, characterised by the fact that the catalyst is the compound of claim 1, eventually in the presence of triphenylphosphine, at a pressure of 1 to 10 kg/cm2 and a temperature from 20°C to 95°C, in the presence of a solvent inert in the reaction, such as a lower alcohol containing from 1 to 6 carbon atoms.
Printed in the UK for HMSO, D8818935, 5/86, 7102.
Published by The Patent Office, 25 Southampton Buildings, London, WC2A 1AY, from which copies may be obtained.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PT79774A PT79774A (en) | 1984-12-28 | 1984-12-28 | Process to prepare rhodium catalysts and applications thereof |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| GB8526784D0 GB8526784D0 (en) | 1985-12-04 |
| GB2168979A true GB2168979A (en) | 1986-07-02 |
| GB2168979B GB2168979B (en) | 1988-06-22 |
Family
ID=20083593
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB08526784A Expired GB2168979B (en) | 1984-12-28 | 1985-10-30 | A rhodium catalyst and its application |
Country Status (19)
| Country | Link |
|---|---|
| EP (1) | EP0187436B1 (en) |
| JP (1) | JPS61161296A (en) |
| AT (1) | ATE51626T1 (en) |
| AU (1) | AU569164B2 (en) |
| BE (1) | BE903700A (en) |
| CA (1) | CA1245643A (en) |
| CH (1) | CH668427A5 (en) |
| DE (2) | DE3576958D1 (en) |
| DK (1) | DK164815C (en) |
| FR (1) | FR2575473B1 (en) |
| GB (1) | GB2168979B (en) |
| GR (1) | GR852920B (en) |
| HK (1) | HK59889A (en) |
| NL (1) | NL8503207A (en) |
| NO (1) | NO854972L (en) |
| NZ (1) | NZ214376A (en) |
| PT (1) | PT79774A (en) |
| SE (1) | SE460581B (en) |
| ZA (1) | ZA859760B (en) |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| PT74303B (en) * | 1982-01-19 | 1983-08-08 | Joao Emerico Villax | PROCESS FOR THE PREPARATION OF NEW CATALYZERS CONTAINING RHODIUM AND USE THEREOF |
| PT76061A (en) * | 1982-12-30 | 1983-01-01 | Stable homogeneous hydrogenation rhodium catalyst - useful in high yield prodn. of doxycycline by stereospecific hydrogenation | |
| DE3769977D1 (en) * | 1987-03-25 | 1991-06-13 | Plurichemie Anstalt | RHODIUM-CONTAINING HYDRATION CATALYSTS. |
| US4902447A (en) * | 1988-10-28 | 1990-02-20 | Ranbaxy Laboratories Limited | Process for the production of alpha-6-deoxytetracyclines and hydrogenation catalyst useful therein |
| PT91333B (en) * | 1989-07-31 | 1995-05-04 | Hovione Sociedade Quimica Sa | PROCESS FOR THE PREPARATION OF A RODIO COMPLEX |
| DE19507018A1 (en) * | 1995-03-01 | 1996-09-05 | Bayer Ag | Process for the preparation of ivermectin |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0086046A1 (en) * | 1982-01-19 | 1983-08-17 | Plurichemie Anstalt | A process for the preparation of alpha-6-DEOXYTETRACYCLINES |
-
1984
- 1984-12-28 PT PT79774A patent/PT79774A/en active IP Right Revival
-
1985
- 1985-07-15 EP EP85305045A patent/EP0187436B1/en not_active Expired - Lifetime
- 1985-07-15 AU AU45010/85A patent/AU569164B2/en not_active Ceased
- 1985-07-15 DE DE8585305045T patent/DE3576958D1/en not_active Expired - Lifetime
- 1985-07-15 AT AT85305045T patent/ATE51626T1/en not_active IP Right Cessation
- 1985-07-16 CA CA000486869A patent/CA1245643A/en not_active Expired
- 1985-10-30 GB GB08526784A patent/GB2168979B/en not_active Expired
- 1985-11-19 DK DK533185A patent/DK164815C/en not_active IP Right Cessation
- 1985-11-21 NL NL8503207A patent/NL8503207A/en active Search and Examination
- 1985-11-22 BE BE0/215904A patent/BE903700A/en not_active IP Right Cessation
- 1985-11-27 FR FR858517511A patent/FR2575473B1/en not_active Expired
- 1985-11-28 NZ NZ214376A patent/NZ214376A/en unknown
- 1985-12-04 GR GR852920A patent/GR852920B/el unknown
- 1985-12-06 SE SE8505766A patent/SE460581B/en not_active IP Right Cessation
- 1985-12-11 NO NO854972A patent/NO854972L/en unknown
- 1985-12-17 CH CH5365/85A patent/CH668427A5/en not_active IP Right Cessation
- 1985-12-20 ZA ZA859760A patent/ZA859760B/en unknown
- 1985-12-20 DE DE19853545395 patent/DE3545395A1/en not_active Withdrawn
- 1985-12-27 JP JP60293376A patent/JPS61161296A/en active Granted
-
1989
- 1989-07-27 HK HK598/89A patent/HK59889A/en not_active IP Right Cessation
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0086046A1 (en) * | 1982-01-19 | 1983-08-17 | Plurichemie Anstalt | A process for the preparation of alpha-6-DEOXYTETRACYCLINES |
Also Published As
| Publication number | Publication date |
|---|---|
| GB2168979B (en) | 1988-06-22 |
| SE8505766D0 (en) | 1985-12-06 |
| JPS61161296A (en) | 1986-07-21 |
| DE3576958D1 (en) | 1990-05-10 |
| SE460581B (en) | 1989-10-30 |
| EP0187436A1 (en) | 1986-07-16 |
| EP0187436B1 (en) | 1990-04-04 |
| DE3545395A1 (en) | 1986-07-03 |
| AU569164B2 (en) | 1988-01-21 |
| PT79774A (en) | 1985-01-01 |
| NO854972L (en) | 1986-06-30 |
| JPH0380149B2 (en) | 1991-12-24 |
| BE903700A (en) | 1986-03-14 |
| DK164815B (en) | 1992-08-24 |
| ATE51626T1 (en) | 1990-04-15 |
| GB8526784D0 (en) | 1985-12-04 |
| GR852920B (en) | 1986-04-07 |
| CH668427A5 (en) | 1988-12-30 |
| NZ214376A (en) | 1988-09-29 |
| DK533185A (en) | 1986-06-29 |
| NL8503207A (en) | 1986-07-16 |
| CA1245643A (en) | 1988-11-29 |
| FR2575473A1 (en) | 1986-07-04 |
| SE8505766L (en) | 1986-06-29 |
| FR2575473B1 (en) | 1989-12-01 |
| AU4501085A (en) | 1986-07-03 |
| HK59889A (en) | 1989-08-04 |
| ZA859760B (en) | 1986-09-24 |
| DK164815C (en) | 1993-01-04 |
| DK533185D0 (en) | 1985-11-19 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PE20 | Patent expired after termination of 20 years |
Effective date: 20051029 |